ABSTRACT AD is the most prevalent age-related neurodegenerative disorder and leading cause of dementia, affecting ~5.7 million people in the U.S. Despite decades of research, treatment options remain limited, and the handful of available pharmacological approaches target single proteins involved in relatively late disease stages and only offer marginal clinical improvements. There is a critical need for new mechanistic insight into AD pathogenesis to develop more effective treatment strategies. Interestingly, obesity, diabetes, and metabolic syndrome all are associated with a heightened risk of developing cognitive dysfunction, including AD. Theories explaining this connection, including impaired brain insulin signaling and insulin resistance, mitochondrial dysfunction, disturbances in lipid and cholesterol metabolism, and perturbed brain energy metabolism, represent important contributory mechanisms and novel therapeutic targets in AD. For our parent R24-funded activities, we are utilizing a well-characterized Pima Indian cohort of over 250 subjects which has been followed over several decades for the development and progression of type 2 diabetes, obesity, and diabetic complications affecting the nerve, kidney, and eyes. Our ongoing analyses include genome-wide and targeted gene studies and transcriptomic, proteomic, lipidomic, and metabolomic profiles for this cohort. In this supplement, our objective is to expand our investigations to the central nervous system (CNS) and assess cognition and brain morphology in the same Pima Indian cohort to gain insight into the mechanisms underlying the increased risk of AD and related dementias associated with diabetes and other metabolic conditions. We hypothesize that cognitive impairment and structural changes in the brain associate with diabetes and diabetic complications. To test this hypothesis, Aim 1 will assess cognition and brain morphology in Pima Indians using the NIH Toolbox Cognitive Battery and an Alzheimer's Disease Neuroimaging Initiative (ADNI) brain MRI to determine the extent of cognitive impairment and changes in brain structure that occur in diabetes. Aim 2 will then identify specific associations between CNS impairment and complications of diabetes using an integrated systems biology approach that will correlate the metabolic and genome-wide DNA, RNA, protein, and lipid profiles acquired through our parent R24 grant with the present cognition and brain morphology data. We will also determine if the profiles can predict the progression of CNS impairment to identify novel biomarkers of disease. Together, these studies will enhance our understanding of the link between cognitive impairment, structural brain changes, and diabetes, and provide new insight into the pathogenesis of AD and related dementias. Successful completion of our proposed studies will therefore have significant impact by supporting the identification of novel biomarkers and the development of mechanism-driven therapies for AD and related dementias associated with diabetes.